Our broad long-term objective is to address the mechanisms by which species barriers and strain specificities control the pathogenesis and transmission of chronic wasting disease (CWD), a contagious disease of deer and elk belonging to a group of fatal, transmissible neurodegenerative disorders of animals and humans caused by prions. Our major objectives are to use proven transgenic (Tg) approaches to study the means by which primary structure elements of the prion protein (PrP) and prion strain properties influence CWD transmission barriers, to address the origins of CWD and the prevalence of CWD strains, and to determine the mechanism of prion transmission among cervids. Three Specific Aims are proposed: (1) To use Tg mice expressing cervid (Cer) PrP [Tg(CerPrP)] that simulate disease in deer and elk to study the mechanisms of CWD transmission among cervids and sub-clinical CWD replication in the absence of accumulation of conventional forms of pathogenic PrP;(2) To use Tg approaches to assess the influence of CWD strain variation and CerPrP polymorphisms on CWD pathogenesis and to address the disease-causing potential of CWD strains in other species;and, (3) To probe the molecular basis of species-dependent CWD transmission barriers using novel chimeric murine/CerPrP constructs and an innovative combination of Tg approaches and in vitro PrP amplification. Addressing the mechanism of CWD transmission will lead to better CWD control in cervid populations and allow more accurate assessments of the risks posed to humans and livestock from exposure to CWD. The proposed studies will also further our understanding of the general molecular events underlying prion propagation, species barriers and prion strains that will ultimately result in rational therapeutic and diagnostic approaches for human and animal prion diseases and will provide important information about the molecular nature of the infectious agent in the contexts of clinical and sub-clinical prion disease.